Over the years, numerous methods have been proposed for improving the stability and delivery of biologically active agents. Challenges associated with the formulation and delivery of pharmaceutical agents can include poor aqueous solubility of the pharmaceutical agent, toxicity, low bioavailability, instability, and rapid in-vivo degradation, to name just a few. Although many approaches have been devised for improving the delivery of pharmaceutical agents, no single approach is without its potential drawbacks. For instance, commonly employed drug delivery approaches aimed at solving or at least ameliorating one or more of these problems include drug encapsulation, such as in a liposome, polymer matrix, or unimolecular micelle, covalent attachment to a water-soluble polymer such as polyethylene glycol, use of gene targeting agents, formation of salts, and the like.
Covalent attachment of a water-soluble polymer can improve the water-solubility of an active agent as well as alter its pharmacological properties. Certain exemplary polymer conjugates are described in U.S. Pat. No. 7,744,861, among others. In another approach, an active agent having acidic or basic functionalities can be reacted with a suitable base or acid and marketed in salt form. Over half of all active molecules are marketed as salts (Polymorphism in the Pharmaceutical Industry, Hilfiker, R., ed., Wiley-VCH, 2006). Challenges with salt forms include finding an optimal salt, as well as controlling solid state behavior during processing. Biopharmaceutical salts can be amorphous, crystalline, and exist as hydrates, solvents, various polymorphs, etc. Interestingly, rarely are salt forms, let alone mixed acid salt forms, of polymer conjugates used in drug formulations.
Another challenge associated with preparing active agent conjugates of water-soluble polymers waters is the ability to prepare relatively pure water-soluble polymers in a consistent and reproducible method. For example, poly(ethylene glycol) (PEG) derivatives activated with reactive functional groups are useful for coupling to active agents (such as small molecules and proteins), thereby forming a conjugate between the PEG and the active agent. When an active agent is conjugated to a polymer of poly(ethylene glycol) or “PEG,” the conjugated active agent is conventionally referred to as having been “PEGylated.”
When compared to the safety and efficacy of the active agent in the unconjugated form, the conjugated version exhibits different, and often clinically beneficial, properties. The commercial success of PEGylated active agents such as PEGASYS® PEGylated interferon alpha-2a (Hoffmann-La Roche, Nutley, N.J.), PEG-INTRON® PEGylated interferon alpha-2b (Schering Corp., Kennilworth, N.J.), and NEULASTA® PEG-filgrastim (Amgen Inc., Thousand Oaks, Calif.) demonstrates the degree to which PEGylation has the potential to improve one or more properties of an active agent.
In preparing a conjugate, a polymeric reagent is typically employed to allow for a relatively straightforward synthetic approach for conjugate synthesis. By combining a composition comprising a polymeric reagent with a composition comprising the active agent, it is possible—under the appropriate reaction conditions—to carry out a relatively convenient conjugate synthesis.
The preparation of the polymeric reagent suitable to the regulatory requirements for drug products, however, is often challenging. Conventional polymerization approaches result in relatively impure compositions and/or low yield. Although such impurities and yields may not be problematic outside the pharmaceutical field, safety and cost represent important concerns in the context of medicines for human use. Thus, conventional polymerization approaches are not suited for the synthesis of polymeric reagents intended for the manufacture of pharmaceutical conjugates.
In the case of multiarm polymers, there is a dearth of available, desirable water soluble polymers that have well controlled and well defined properties with the absence of significant amounts of undesirable impurities. Thus one can readily obtain, for example, a high molecular weight multiarm poly(ethylene glycol) but drug conjugates manufactured from commercial polymers may have significant amounts (i.e. >8%) of polymer-drug conjugate having either very low or very high molecular weight biologically active impurities. This extent of active impurities in a drug composition may render such compositions unacceptable and thus render approval of such drugs challenging if not impossible.